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New modes and mechanisms of negative regulation of LIN-12/Notch in C. elegans

线虫中LIN-12/Notch负调控的新模式和新机制

基本信息

批准号：
9146963
负责人：
Iva S Greenwald
金额：
$ 34.16万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-21 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9146963
关键词：
Address Adopted Aging Animals Binding Biochemical Biological Assay Caenorhabditis elegans Cancer Etiology Cancer Patient Candidate Disease Gene Cell Communication Cell Culture Techniques Cells Complex Development Diagnostic Disease Down-Regulation Endocytosis Ensure Environment Epidermal Growth Factor Receptor Experimental Designs Feedback Gene Targeting Genes Genetic Goals Health Homeostasis Human Human Development Image Immune System Diseases Individual Injury Insulin Knowledge Larva Lead Life Ligands Lobular Neoplasia Malignant Neoplasms Mammalian Cell Mediating Membrane Mission Mutate Mutation Nuclear Oncogenes Oncogenic Pathway interactions Pattern Phosphotransferases Physiology Positioning Attribute Property RNA interference screen Receptor Activation Refractory Regulation Reporter Genes Resistance Role Signal Pathway Signal Transduction Somatomedins Spottings Stem cells Surface Syndrome System Tertiary Protein Structure Textbooks Therapeutic Time Tissues Trans-Activators Transgenes Tumor Suppressor Proteins United States National Institutes of Health Work base cell fate specification chemotherapy developmental disease gene discovery genetic analysis human disease in vivo in vivo imaging insight mutant nervous system disorder notch protein novel strategies precursor cell prevent receptor response stem tool trafficking transcription factor transcriptomics

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this application is to elucidate different mechanisms for negative regulation of Notch signaling. Notch is the eponymous receptor in a major signaling system for cell-cell interactions and cell fate specification in animl development. Regulating Notch signaling appropriately--in space, time, strength or duration--is critically important for normal development. Furthermore, aberrant Notch activity has been implicated in many different cancers, as well as in developmental, immune, and neurological disorders. Thus, the proposed work has many implications for human health. The deeper understanding of developmental mechanism has great potential for developing diagnostic and therapeutic tools for human disease, a central mission of the NIH. Our past work on LIN-12/Notch signaling in C. elegans has afforded many fundamental insights into conserved roles, mechanisms, and regulation of Notch signaling. We expect that our continued work in this system will continue to reveal mechanisms of general relevance, and particular aspects of experimental design were chosen to maximize this prospect. Each aim of this application explores different ways LIN-12/Notch activity and stability is modulated in a textbook developmental paradigm in which six multipotential precursor cells adopt one of three distinct fates through LIN-12/Notch-mediated cell-cell interactions. The patterning is precise and robust, reflecting tight spatial and temporal control of LIN-12/Notch activity and multiple modes for integrating LIN-12/Notch activity with other conserved signaling pathways. In Aim 1, we propose to characterize new kinases we identified in a targeted screen for negative regulators and another gene, first identified by a mutation in a cancer patient, we showed acts as a negative regulator in C. elegans. To assess their functional conservation in Notch regulation, we will perform a human cell assay. In Aim 2, we propose to investigate LIN-12/Notch endocytic trafficking and its negative regulation by EGF Receptor activity in developmental patterning. EGF Receptor, like Notch, is an important oncogene, and crosstalk between these pathways occurs in cancer as well as in normal development. In Aim 3, we propose to elucidate how activated nuclear LIN-12/Notch is inhibited by EGF receptor during developmental patterning and by Insulin/Insulin-like Signaling during quiescence in response to unfavorable environment. Quiescence is a fundamental property of critical importance for human health, allowing stem cells to persist over prolonged periods in a competent state so as to be available to repopulate tissues when cells are lost to aging, injury or disease, and for cancer, quiescent stem-like cells are believed to be resistant to standard chemotherapy. Together, these aims will provide much new information about negative regulation of a fundamental signaling pathway in development and disease, in accord with the mission of the NIH.